3-Substituted indoles from the interrupted Nazarov reaction. Overall yields are reported for the three steps: nucleophilic addition of propargyllithium anion 2 to the enamide, formation of the silyl enol ether, and cyclization. Yields in parentheses refer to the overall yield for the two-step process proceeding through the propargyl vinyl ketone.

Allenyl vinyl ketones undergo a particularly rapid Nazarov cyclization.– A few years ago, we reported a cascade process that involved the isomerization of propargyl vinyl ketones such as 3 () on silica gel in the presence of a primary or secondary amine. Ketones 3 are easily prepared from the addition of propargyllithium nucleophile 2 to morpholino enamides like 1. Exposure of 3 to a small excess of cyclohexylamine 4 and dry silica gel in the absence of solvent led to a single diastereoisomer of 7 in 63% overall yield from enamide 1. Cyclohexylamine performs two functions in this process. It catalyzes the isomerization of 3 to allenyl vinyl ketone 5, and it acts as a nucleophile to intercept cation 6. This is an example of an interrupted Nazarov process, a reaction type that has been extensively developed and refined in recent years through the efforts of the West group.,

Simply agitating a mixture of ketone 3, indole 8, and silica gel led to no reaction. It is not surprising that the conditions that had proven to be successful for amines failed since indole is not basic enough to catalyze the first step, isomerization of 3 to 5. In earlier work, we had observed that in the absence of an external nucleophile some Lewis acids were effective in catalyzing the conversion of 3 to 11 () in solution, suggesting that 5 had been formed as an intermediate. A series of Lewis acids (Sc(OTf)3, Cu(OTf)2, TMSOTf, BF3·Et2O, silica gel) and solvents (CH3CN, CH2Cl2, THF, PhH, EtOAc, DMF, DMSO) were screened in the reaction of 3 with 8. The best results were observed with 20 mol % of Sc(OTf)3 in acetonitrile with 1.25 equiv of indole. Under these conditions, the anticipated product 9 was formed in 48% overall yield from 1. The stereochemistry of 9 is controlled by nucleophilic attack of indole trans to the C4 methyl group in cyclic cation 6 (see ). The stereochemical assignment of 9 was made on the basis of NOE experiments. Irradiation of the C4 methyl group in the 1H NMR spectrum of 9 led to enhancement of the signal due to the C5 methyl group, indicating that the two methyl groups are cis. Irradiation of the C4 methine led to enhancement only of the signal due to the C4 methyl group. However, the reaction leading to 9 was very slow, requiring several days for the complete consumption of 3, and led to a large amount of byproduct 10 as well as smaller amounts of cross-conjugated cyclopentenone 11.

We were never successful in completely eliminating 10 from the reactions of 3. A faster reaction was desirable for this reason and also to make the method more practical for synthesis. Since allenyl vinyl ketones once formed undergo very fast cyclization, we modified our reaction conditions to ensure the rapid generation of the allene. Accordingly, ketone 3 was converted to trimethylsilyl enol ether 14 by treatment with LDA at −78 °C followed by trimethylsilyl chloride (). Enol ether 14 was formed as a single geometrical isomer to the limits of detection by 1H NMR, presumed to be Z. Exposure of 14 to a 25% molar excess of 5-methoxyindole 15 in dichloromethane with 20 mol % of Sc(OTf)3 resulted in a fast (1.5–3 h) reaction that led to the desired product 16 in 72% overall yield from enamide 1. Under these reaction conditions, none of the bisindole byproduct was observed in the product mixture, and neither was ketone 3, indicating that protonation of 14 must occur exclusively or nearly so at the distal acetylenic carbon atom. This leads directly to the pentadienyl cation that cyclizes. In the absence of an external nucleophile, proton loss terminates the process and leads to 11. Since the reaction is catalyzed by a proton, the role of Sc(OTf)3 may be to activate some trace of water that is present, thereby converting it into a strong Bronsted acid. Since we did not go to extraordinary lengths to ensure rigorously anhydrous reaction conditions, this seems plausible. The fact that no reaction takes place when crushed 4 Å molecular sieves are added to the reaction mixture lends support to this hypothesis since the sieves would scavenge both water and Bronsted acids. The reaction of 14 with 15 can certainly be catalyzed by Bronsted acid since treatment with 20 mol % Tf2NH also leads to product 16. We did not screen Bronsted acids because the Sc(OTf)3-catalyzed process worked so well. Of the solvents we did screen (PhH, CH3CN, CH2Cl2), reactions in dichloromethane at moderate concentration (ca. 0.35 M) were the cleanest.

To demonstrate some of the options to further functionalize the products, the reactions that are summarized in were carried out. Rapid cleavage of the TIPS group from 26 took place with n-Bu4NF in THF at room temperature (81% yield). Subsequent deprotonation of the methyl group in 30 with LDA at −78 °C was followed by trapping of the extended enolate anion with ethyl cyanoformate or with paraformaldehyde, leading to ethyl ester 31 or alcohol 32 in 70% and 60% yield, respectively. Surprisingly, all attempts to trap the lithium enolate derived from 30 with alkyl halides failed, leading only to unreacted ketone. However, changing the base from LDA to KHMDS and treatment of the potassium enolate of 30 with iodomethane led to the desired product 33 in 90% yield. This is quite puzzling since a key step in our synthesis of (±)-terpestacin is alkylation of the lithium enolate derived from 34 with iodomethane. This reaction takes place in high yield at C23 (terpestacin numbering) under conditions that are identical to those used for 30. It may be the case that the lithium enolate derived from 30 is stabilized to a greater extent through bidentate chelation than the enolate of 34, due to conformational constraints in 34 that are imposed by the acetonide ring and that are absent in the enolate of 30.